This is an application for an integrative research effort to design complement therapeutics using computational, physicochemical, and biochemical approaches. The proposed project will accomplish this by bringing together investigators with leading expertise in different fields (complement biology, structural biology, combinatorial and global optimization) who share the same appreciation for the complexity of biological processes and are committed to addressing and elucidating the structural elements involved in protein-protein interactions. The specific contribution of each PI in this project is (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, and (iii) synthesis and functional characterization of peptides and peptidomimatics to design novel therapeutics. The principal investigators have a long history of scientific interaction that they wish to maintain and expand through the successful funding of this application. Our target is the complement system, and specifically its component C3, and the C3a, and C5a anaphylatoxins. The basis of the proposed work is the recently developed two-stage integrated structural, computational, and experimental protein design method, used not only to select and rank sequences for a particular fold but also to validate the specificity of the fold for these selected sequences. The sequence selection phase relies on flexible templates provided through NMR experiments and analysis, and on an integer linear programming (ILP) model with several constraint modifications that improve the tractability of the problem and enhance its deterministic convergence to the global minimum. In addition, a rank-ordered list of low lying energy sequences are identified, along with the global minimum energy sequence. Once such a subset of sequences have been identified, the fold validation stage is employed to verify the stabilities of the designed sequences through a deterministic global optimization approach that allows for backbone flexibility. The selection of the best designed sequences is based on rigorous quantification of free energy-based probabilities, and it is followed with the experimental validation of structure by NMR and through measuring the complement modulating activities of synthesized compounds. We believe that this methodology is general enough that we expect it will eventually be of broad use in the field of peptide-based drug design. [unreadable] [unreadable] [unreadable] [unreadable]